Project Summary Antiretroviral pre-exposure prophylaxis (PrEP) with tenofovir disoproxyl fumarate (TDF)/ emtricitabine (TDF/FTC) reduces the risk of HIV acquisition in high-risk HIV-uninfected individuals. However, a major critique of TDF/FTC PrEP is the potential for kidney and bone toxicity. Although overt kidney toxicity is rare, subclinical kidney injury is common in HIV-infected individuals on TDF-containing antiretroviral therapy. TDF has also been associated with altered bone metabolism, including declines in bone mineral density, increased markers of bone turnover, and increased fracture risk, but the relationship with kidney injury is not known. We hypothesize that TDF/FTC PrEP causes subclinical kidney injury in HIV-uninfected adults, and that subclinical proximal tubular injury promotes clinically relevant declines in kidney function and alterations in bone mineral metabolism. We will investigate this hypothesis using data and banked specimens from the Partners PrEP Study, a randomized, placebo-controlled trial that demonstrated efficacy of TDF/FTC PrEP in 4758 HIV-uninfected members of heterosexual HIV-1 serodiscordant couples in Uganda and Kenya. The prospective documentation of serum creatinine in all Partners PrEP Study participants and the measurement of noninvasive biomarkers of proximal tubular dysfunction and bone turnover in a nested subgroup of participants will allow us to determine whether TDF/FTC PrEP causes clinically relevant kidney injury and alterations in bone metabolism. In nested case-control studies, we will determine whether subclinical proximal tubular injury is a risk factor for decline in glomerular filtration rate or increased bone turnover. We will also leverage the unique opportunity to study cumulative TDF-induced kidney injury in healthy adults in order to identify urine biomarkers of drug-induced kidney injury with potential applications in drug development and toxicity monitoring. The results of the proposed research are expected to have significant implications for the implementation of antiretroviral PrEP and alternative approaches to HIV prevention. The identification of new biomarkers of drug- induced kidney injury is expected to accelerate future drug development for HIV and other chronic diseases.